Peimisine-sulfide improves inflammation caused by copper sulfate through inhibiting ferroptosis using zebrafish embryos.

Peimisine (PMS), a primary bioactive compound in Fritillaria, exhibits promising anti-inflammatory properties. However, its low water solubility limits bioavailability. Sulfonation of PMS yields peimisine-sulfide (PMS-S), a derivative with enhanced solubility, though the biosafety profiles of both compounds remain unclear. Furthermore, the anti-inflammatory mechanism of PMS-S has yet to be elucidated. To address these gaps, we first conducted acute toxicity assays in zebrafish embryos. While 100 µmol/L PMS induced significant toxicity, thioylation to PMS-S eliminated adverse effects at concentrations up to 100 µmol/L (0.1-100 µmol/L). Next, we established a copper sulfate (CuSO₄)-induced inflammatory model in transgenic zebrafish Tg (mpeg1: EGFP). PMS-S treatment suppressed macrophage migration and aggregation at injury sites. Additionally, PMS-S reduced reactive oxygen species (ROS) levels and downregulated ferroptosis-related genes (acsl4b and fthl28), suggesting inhibition of ferroptosis as a potential anti-inflammatory mechanism. In conclusion, thioylation not only enhances the biosafety of PMS but also confers anti-inflammatory activity via ferroptosis suppression. These findings provide a mechanistic foundation for the clinical development of PMS-S as a therapeutic agent.